Plasma cell diversity

Context:

 In their great majority, existing vaccines promote protective immunity thanks to their capacity to generate humoral immune memory, i. e. on antibody (Ab) production. It has been known since the late nineties that humoral memory relies on two major cell types designated as memory B lymphocytes (mBCs) and long-lived memory plasma cells (mPCs). mPCs are responsible for the long-term production of protective or seroneutralizing Abs long after Ag or pathogen clearance. They constitute the first barrier that opposes reinfection. mBCs come into play when this serological memory  is overwhelmed by the pathogen via their capacity to rapidly differentiate into effector plasma cells producing high-affinity Abs. One of the key recent conceptual advance in the field is the discovery in 2009 that B cell memory is multilayered and emcompasses several B cell subsets programmed to exert distinct functions.  The actual concept is that certain attributes that were classically assigned to memory B cells such as longevity, capacity to rapidly generate a large pool of effector cells are in fact functionalities which are restricted to given memory cell subtypes. Likewise, the PC compartment is also heterogeneous. We have described that the PC pool is subdivided into two major subtypes : conventional PCs (cPCs) that lack surface Igs and secrete IgG, and non conventional PCs (ncPCs) that secrete IgM or IgA and express a functional Ag receptor (BCR) (Blanc et al. Nature Comms, 2016).

Objectives:

 Our working hypothesis is that cPCs and ncPcs originate from distinct developmental processes and that the latter population is endowed with a dual identity that translates into a double function : i) a canonical Ig secretion capacity and ii) a non-canonical cytokine production ability. Our preliminary results suggest that the BCR signaling pathway in ncPCs behaves as a molecular rheostat that controls the balance between their canonical and non-canonical biological function. The main goal of our project is to gain a better understanding of the contribution of ncPCs to the humoral response elicited by vaccines or bacterial infection.  We have developed different mouse models in which components of the BCR signaling pathway are selectively invalidated in PCs (BCR-less PCs). Our study relies on the following experimental approaches :  i) impact of the PC-targeted BCR invalidation on in vivo humoral responses, ii) dissection of PC heterogeneity using multiparameter flow cytometry (Spectral technology) and transcriptomic analysis by RNAseq, iii) comparative analysis of the BCR signaling pathway in B cells and ncPCs.

Internalization of a particulate Ag by ncPCs:

Visualization by the Image Stream X technology of the internalization of a particulate Ag (in red) by ncPCs (Blimp-1⁺, green). LAMP-1+ endocytic compartments (yellow). Phosphorylated endosomal kinase Erk (violet).